Phase 1a/1b study of FOR46, an antibody drug conjugate (ADC), targeting CD46 in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rahul Raj Aggarwal, Jacqueline Vuky, David James VanderWeele, Matthew Rettig, Elisabeth I. Heath, Tomasz M. Beer, Jiaoti Huang, Nela Pawlowska, Ryan Sinit, Jill Abbey, Bin Liu, Marc Nasoff, Andrew Dorr, Eric Jay Small
Journal: Journal of Clinical Oncology (2022)

3001 Background: FOR46, a fully human antibody (ab) conjugated to monomethyl auristatin E (MMAE), targets a tumor selective epitope of CD46, which is highly expressed in mCRPC and treatment-emergent small cell neuroendocrine cancer (t-SCNC). CD46 is enriched in tumor cells upon treatment with androgen signaling inhibitors (ASI). Following dose escalation (Phase 1a), dose expansion was undertaken in 2 cohorts (Phase 1b): 1) Pts with de novo or t-SCNC and 2) pts with mCRPC without a t-SCNC component. Pts with adenocarcinoma enrolled in dose escalation and expansion are included in this analysis. Methods: Eligible pts had mCRPC, with progression on at least 1 ASI, with no prior chemotherapy for CRPC. Phase 1a pts received FOR46 0.1-3.0 mg/kg IV Q3 weeks (wks). The primary objectives in phase 1a were to assess adverse effects (AEs) and select the phase 1b dose; and in phase 1b to assess efficacy. For phase 1b, tumor biopsy in the CRPC setting for assignment to the 2 cohorts was required. CD46 expression was not required for inclusion in the expansion cohort, but was evaluated using a non-epitope specific CD46 polyclonal ab. Histology and CD46 expression were centrally reviewed. Results: Thirty-three pts were enrolled in phase 1a and 10 in phase 1b (including 6 treated in ph1a at the expansion dose or higher). Overall, 36 pts were treated at doses &gt; 1.2 mg/kg. Following excess toxicity in pts with body mass indices &gt; 30 (3 of 3 with Gr 4 neutropenia and 1 of 3 with Gr 3 fatigue at 2.4 mg/kg), further dosing was calculated using adjusted body weight (AJBW) rather than actual weight, allowing escalation to 3.0 mg/kg. The 2.7 mg/kg dose by AJBW was determined to be the MTD and phase 1b dose. The most common AEs at the 2.7 mg/kg dose were neutropenia (77% Gr 3 or 4), infusion reactions (37%, all &lt; Gr 2), fatigue (31%, all &lt; Gr 2) and peripheral neuropathy (24%, all &lt; Gr 2)). Fourteen of 31 evaluable pts (45.2%) at &gt; 1.2 mg/kg achieved a PSA 50 response with 10 (32.3%) confirmed. Five pts were not evaluable for PSA response; 3 had no post-baseline PSA and 2 had baseline PSA &lt; 1 ng/mL. The median duration of confirmed PSA 50 response is &gt;16 wks (range 6-48+ wks, with 4 ongoing at 12, 24, 25 and 48 wks). 18 pts had measurable lesions; 8 of 18 (44.4%) had tumor regression, with 4 (22.2%) confirmed partial responses (PR). The median duration of response is &gt; 14 wks (range 9 -31+ weeks with 2 ongoing at 13 and 31 wks). Eight pts were evaluable for CD46 expression with a median H-score of 245 (range 0-300). Two pts with PRs had H-scores of 15 and 300; 4 with confirmed PSA 50 had H-scores of 10, 15, 40 and 300. Conclusions: FOR46, a novel ADC targeting CD46, demonstrates clinical activity in mCRPC pts, with an acceptable safety profile, similar to other MMAE-containing ADCs. FOR46 merits further investigation in pts with mCRPC, alone and in combination with agents that enhance CD46 expression. Clinical trial information: NCT03575819.